Sulforaphane prevents pulmonary damage in response to inhaled arsenic by activating the Nrf2-defense response

Abstract

Exposure to arsenic is associated with an increased risk of lung disease. Novel strategies are needed to reduce the adverse health effects associated with arsenic exposure in the lung. Nrf2, a transcription factor that mediates an adaptive cellular defense response, is effective in detoxifying environmental insults and prevents a broad spectrum of diseases induced by environmental exposure to harmful substances. In this report, we tested whether Nrf2 activation protects mice from arsenic-induced toxicity. We used an in vivo arsenic inhalation model that is highly relevant to low environmental human exposure to arsenic-containing dusts. Two-week exposure to arsenic-containing dust resulted in pathological alterations, oxidative DNA damage, and mild apoptotic cell death in the lung; all of which were blocked by sulforaphane (SF) in an Nrf2-dependent manner. Mechanistically, SF-mediated activation of Nrf2 alleviated inflammatory responses by modulating cytokine production. This study provides strong evidence that dietary intervention targeting Nrf2 activation is a feasible approach to reduce adverse health effects associated with arsenic exposure.

Tanshinone I Activates the Nrf2-Dependent Antioxidant Response and Protects Against As(III)-Induced Lung Inflammation In Vitro and In Vivo

“…For example, SF has been shown to limit organ toxicity of As(III) in vivo when As(III) was administered through drinking water (25). More recently, we have shown that Nrf2 status determines the sensitivity of mice to As(III)-induced lung damage and that Nrf2 modulation using SF prevents inflammatory tissue damage in an in vivo As(III) inhalation model that is relevant to low environmental human exposure to As(III)-containing dusts (62).…”

“…In addition, reduced expression of Keap1, due to hypermethylation or loss of heterozygosity, also leads to high basal levels of Nrf2 in certain cancers (32,44). As(III) itself is an Nrf2 activator and has been shown to induce the Nrf2 pathway in many cell lines in vitro and in the liver, bladder, and lung when As(III) was administered through drinking water or inhaled particles in vivo (25,33,62). It is perplexing how could both beneficial chemopreventive compounds and harmful arsenicals induce Nrf2.…”

“…7B). Participation of CD4 + T cells, including Th1 and Th2 cells, in the As(III)-mediated inflammation response has recently been revealed (11,12,62). Therefore, we employed real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect the mRNA levels of Th2 cytokines (IL-13 and IL-4) and Th1 cytokines (IL-2 and interferon gamma [IFNc]) (Fig.…”

Artemisitene activates the Nrf2‐dependent antioxidant response and protects against bleomycin‐induced lung injury

“…Targeting Nrf2 activation with small molecular chemical inducers can enhance the body's antioxidant ability, and has been shown in experimental models to effectively protect the body from tissue damage caused by environmental insults, preventing disease or inhibiting the progression of diseases related to oxidative stress, including diabetes, cancer, cardiovascular diseases, neurodegenerative diseases, chronic obstructive pulmonary disease, pulmonary fibrosis, and inflammation (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Although the Nrf2 program is usually regarded as beneficial, recent work has suggested that high constitutive levels of Nrf2 also bring its "dark" effects (24)(25)(26)(27).…”

“…Many chemopreventive compounds have been identified as Nrf2 activators so far, and some newly identified Nrf2 activators are becoming potential novel chemopreventive compounds that have been shown in experimental models to effectively prevent disease or inhibit the progression of diseases related to oxidative stress (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). To date, most identified Nrf2 activators are plant-derived chemicals, including sulforaphane (SF), tanshinone I, curcumin, butylated hydroxyanisole, and so on, some of which are in our diet (11,30,31).…”